Stroke is a leading cause of morbidity in the U.S. but identification of treatment strategies to improve outcome is limited by the incomplete understanding of the mechanisms of recovery. Motor cortex reorganization of the lesioned hemisphere (lesioned M1) plays a major role in post-stroke recovery of motor function;hence the importance for further development of rehabilitative strategies that utilize this potential for recovery. Non-invasive cortical stimulation can enhance the beneficial effects of motor training on performance and functional plasticity of motor cortex. Among the different approaches used in these studies, Hebbian-type M1 stimulation is particularly intriguing, as it seems to be more effective when compared to random M1 stimulation. There is emerging evidence that motor training or cortical stimulation related improvement of function are associated with increases in the grey matter of targeted brain areas. While there is therefore some evidence supporting structural reorganization in human M1 in response to motor learning and cortical stimulation, the mechanisms underlying these changes and their relationship to functional plasticity are not known. A better understanding of the sequences of events is critical to development of optimal therapeutic interventions to improve recovery following stroke. In Specific Aim 1, we will determine if repeated exposure to training combined with Hebbian-type M1 stimulation enhances functional reorganization in lesioned M1 of stroke patients. In Specific Aim 2, we will determine if repeated exposure to training combined with Hebbian-type M1 stimulation enhances structural reorganization in lesioned M1 of stroke patients. We will then explore the relationship between training related functional and structural cortical reorganization. At the completion of this project, it is our expectation that we will have determined the effect of Hebbian-type stimulation on both, functional and structural brain reorganization, thereby obtaining indirect evidence for the neuronal substrate underlying training related improvement and maintenance of motor function in stroke patients. This knowledge would be expected to have a substantial positive impact on treatment for stroke patients that will significantly improve recovery and would move the field of neurorehabilitation forward. PUBLIC HEALTH RELEVANCE: The research proposed in this study links science to neurorehabilitation practice in stroke patients by establishing the extent to which Hebbian-type stimulation of motor cortex enhances motor performance post-stroke through functional and structural plasticity. These data could then be used to design evidence-based, cost-effective beneficial practice strategies, thereby reducing stroke morbidity and disability.